crossing96/oncoscreening huggingface dataset:
Self-driven electrical triggering system activates tunneling nanotube highways to enhance drug delivery in bladder cancer therapy.	Bladder cancer ranks among the most prevalent malignancies affecting the urinary system worldwide. Despite advances in treatment, poor drug penetration and uncontrolled release continue to impede the effectiveness of chemotherapy for this disease. To overcome these obstacles, we have developed a self-driven electrical triggering system, which leverages intravesical pressure to produce electricity. This electronic trigger system can rapidly transport hydroxycamptothecin through tunneling nanotubes, acting as a high-speed channel, thereby enhancing the drug absorption by tumor cells. Additionally, the voltage generated by this system effectively induces reactive oxygen species (ROS), further promoting the eradication of bladder cancer cells. In orthotopic female animal models of bladder cancer, our results indicate that an intravesical pressure-driven system in the bladder generates electricity to facilitate drug release and rapid diffusion through a tunneling nanotube highway, while also effectively generating ROS to eliminate bladder cancer cells. This self-driven electrical trigger system, coupled with a tunneling nanotube highway to transport drugs, offers renewed hope for bladder cancer treatment. With its potential to transform current therapeutic approaches, this system is poised for deeper exploration in research and clinical settings.	bladder
Molecular classification of nonurothelial histologic subtypes of bladder cancer.	Molecular subtyping of bladder cancer facilitates the development of personalized treatments and predict responses based on disease biology. Classically, bladder cancers have been classified into basal and luminal molecular subtypes. However, recent advances in sequencing techniques have brought more detailed strata at both the genomic and transcriptional level. This has resulted in molecular classifications with greater intrinsic differences among both muscle invasive (MIBCs) and non-muscle invasive bladder cancers (NMIBCs) as well as those differentiating urothelial and nonurothelial tumors. Recently, various groups have developed new or updated existing bladder cancer molecular classification schema. This review summarizes recent progress in molecular classification of nonurothelial histologic subtypes of bladder cancer. These tumors are canonically aggressive with few treatment options other than upfront extirpative surgery and thus represent a key target for novel molecular technology that can accelerate treatment development and improve prognostication.	bladder
β2-integrins as biomarkers in urothelial cancer.	β2-integrins are a family of adhesion proteins expressed in immune cells that play multiple roles in anti-tumor immunity. β2-integrins regulate tumor infiltration of anti-tumorigenic immune cells such as cytotoxic CD8 + T cells and NK cells. However, they also regulate the activity of myeloid cells, such as macrophages, which can have both anti- and pro-tumorigenic properties. The role of β2-integrins in urothelial cancer remains poorly understood. Here, we have investigated the role of different β2-integrins, and their cytoplasmic regulators, in urothelial cancer, by utilizing RNA expression data. We found that ITGAL (encoding for CD11a) and FERMT3 (encoding for the integrin regulator kindlin-3) have a positive correlation with patient survival. EcoTyper analysis revealed increased infiltration of CD8 + T cells and NK cells in ITGAL high samples, but ITGAL or FERMT3 expression did not correlate with response to immunotherapy. In contrast, ITGAM and ITGAX (which encode for myeloid markers CD11b and CD11c) and FLNA (encoding for the integrin regulator filamin A) correlated with poor survival and reduced responsiveness to immunotherapy and critically regulate the tumor myeloid immune landscape (M1/M2 macrophages, cDC1 dendritic cells). Therefore, β2-integrins may be explored in the future as biomarkers to differentiate urothelial cancer patients with different immune landscapes, responding differently to therapy.	bladder
Systemic immunotherapy for BCG unresponsive nonmuscle-invasive bladder cancer.	PURPOSE OF REVIEW: Treatment of Bacillus Calmette-Guérin (BCG)-refractory nonmuscle-invasive bladder cancer (NMIBC) is a significant clinical problem, with limited bladder-sparing strategies. The following review aims to show the recent advances in systemic immunotherapy that are transforming the treatment paradigm in patients with BCG-refractory NMIBC. RECENT FINDINGS: Developing evidence highlights the therapeutic success of immune checkpoint inhibitors, such as pembrolizumab and gene therapy, which received regulatory approval for high-risk BCG-refractory NMIBC. Combination regimens, with immunotherapy combined with intravesical therapy or chemotherapy, are under exploration to enhance treatment efficacy and bypass resistance. The identification of new molecular targets and the development of tailored strategies also depict the fast-paced evolution in this field. SUMMARY: Systemic immunotherapy is now of potential benefit in BCG-refractory NMIBC patients, providing viable bladder-sparing therapies. Our findings have significant implications for clinical practice and enable the transition to individualized, less invasive therapies. More work is required to optimize outcomes, expand therapeutic options, and improve quality of life in this challenging patient population.	bladder
LDHA facilitates immune escape in bladder cancer through H4K5 lactylation-dependent upregulation of PD-L1.	Metabolic reprogramming, characterized by hyperactive glycolysis, is a hallmark of bladder cancer (BCa) progression. Here, we identify lactate dehydrogenase A (LDHA) as a central metabolic node coupling glycolytic flux to epigenetic regulation of the immune checkpoint molecule PD-L1. Transcriptomic and survival analyses reveal that dysregulated glycolytic enzymes, particularly LDHA, correlate with poor prognosis and immunotherapy response in BCa patients. Mechanistically, LDHA-driven lactate production induces histone H4K5 lactylation (H4K5la), facilitated by the acetyltransferase EP300, which directly activates PD-L1 transcription. Depletion of LDHA or EP300 reduces H4K5la levels and suppresses PD-L1 expression. Critically, EP300 knockdown reverses PD-L1 upregulation induced by LDHA overexpression, establishing a causal LDHA-EP300-H4K5la-PD-L1 axis that drives immune evasion. Furthermore, RNA immunoprecipitation and luciferase reporter assays suggest that m6A RNA modification may potentiate LDHA overexpression. Collectively, this work unveils a dual-layered mechanism-metabolic lactate flux and histone lactylation that orchestrates immune evasion in BCa, proposing LDHA and EP300 as actionable targets to restore antitumor immunity.	bladder
Construction of a gene-metabolite-microbiome regulatory network reveals novel therapeutic targets in bladder cancer through multi-omics analysis.	BACKGROUND: Bladder cancer (BLCA) is a prevalent malignancy with substantial consequences for patient health. This study aimed to elucidate the underlying mechanisms of BLCA through integrated multi-omics analysis. METHODS: Tumor and adjacent tissues from BLCA patients underwent transcriptomic, whole-exome sequencing, metabolomic, and intratumoral microbiome analyses. These data were integrated with public datasets to identify key genes, metabolites, and microorganisms. Molecular subtypes were defined by key gene expression and compared for pathways, immune profiles, mutations, immunotherapy response, and drug sensitivity. Prognostic relevance was validated in external cohorts. Single-cell sequencing was applied to reveal cellular localization of key genes. RESULTS: Three key genes (AHNAK, CSPG4, NCAM1), 90 metabolites, and two microbes (Sphingomonas koreensis, Rhodospirillaceae) were identified. Key genes negatively correlated with metabolites but not with microbes. BLCA samples were classified into two molecular clusters with distinct ECM organization, metabolic features, immune checkpoint expression, and therapeutic sensitivity. NCAM1 correlated positively with γδ T cells and negatively with M0 macrophages. Single-cell analysis revealed nine major cell types, with fibroblasts displaying the highest expression of key genes, particularly elevated AHNAK in specific fibroblast subtypes. Drug prediction and docking identified candidate compounds targeting these genes with stable binding potential. CONCLUSION: This comprehensive multi-omics analysis links key genes, metabolites, and microbes to BLCA pathogenesis. Fibroblasts emerge as central regulators, while identified gene-metabolite interactions and microbial associations provide novel insights into tumor heterogeneity. These findings highlight potential biomarkers and therapeutic targets to support precision treatment in BLCA.	bladder
Characterization of cancer-related fibroblasts in bladder cancer and construction of CAFs-based bladder cancer classification: insights from single-cell and multi-omics analysis.	"BACKGROUND: Bladder cancer (BLCA) continues to be a significant cause of cancer mortality in the urinary tract, with therapeutic resistance representing a major barrier to improving patient outcomes. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are pivotal drivers of BLCA progression, contributing to immune evasion and therapy resistance. This study leverages single-cell analysis to delineate CAF subclusters and explore the immune characteristics of CAFs-based BLCA classification. MATERIALS AND METHODS: Signal-cell RNA sequencing (scRNA-seq) datasets were used to identify CAF subpopulations in BLCA, and bulk RNA-seq datasets were used to construct CAFs-based BLCA classification. Next, we comprehensively explored the distinct heterogeneity and characteristics for four CAFs-based BLCA subtypes. Moreover, machine learning algorithms were applied to identify novel potential targets for each subtype, and experimentally validate their effects. RESULTS: This study identified CAFs closely associated with BLCA development based on scRNA-seq datasets. Through further systematic clustering and functional analysis of CAFs, we successfully identified 10 distinct CAF sub-clusters, including PSCA+ Pericyte, ISG15+ Pericyte, ACTA2+ Smooth muscle cell (SMC), ACTG2+ SMC, CCL21+ inflammatory Pericyte, CD74+ apCAF, STMN1+ pCAF, CXCL14+ mCAF, APOD+ iCAF, CFD+ iCAF. The study identified four pCAFs-based BLCA distinct subtypes with different molecular, functional, and immunologic characteristics. C3 exhibited an immune-rich subtype accompanied by poor clinical prognosis, cell death pathway enrichment, higher expression of MHC molecules and co-stimulatory/co-inhibitory molecules. Conversely, C4 subtype has a smaller number of patients and an optimal prognosis, associated with lower levels of cell death pathway enrichment, lower frequency of tumor mutations, and an ""immune desert"" TME. C1 is mainly enriched in metabolism-related pathways, and C2 is mainly enriched in the activation of genome instability pathways, accompanied by more frequent mutations and higher Atezolizumab response. Furthermore, this study identified potential target genes or prognostic markers for each subtype. CONCLUSION: Various heterogeneous CAF subgroups exist in BLCA, which is closely associated with the development of BLCA. This study identified a promising platform for understanding heterogeneity of CAFs-based BLCA subtypes, providing novel insights into the intricate molecular mechanisms of BLCA. Potential target genes for each subtype provide a basis for diagnosis and screening of BLCA patients."	bladder
Grading of bladder cancer: updates, controversies and practical solutions.	Bladder cancer grading provides important prognostic information to clinicians, and the assigned grade is used as a variable in risk stratification models. There have been multiple proposed grading schemes over the last century, with the most widely utilized in contemporary practice being the World Health Organization (WHO) 1973 and 2004 schemes, with WHO 2004 used almost exclusively in North America, and dual grading using both 2004 and 1973 is in widespread use in Europe. Recently, there has been increased interest in hybrid grading schemes for papillary bladder cancer. These combine features from both aforementioned schemes and have demonstrated prognostic performance that exceeds WHO 2004 and WHO 1973. In this article, we review the historical background and new concepts in bladder cancer grading, highlight the opinions and perspectives of clinicians and pathologists, and assess the challenges along with evidence for and against different grading schemes. We discuss the potential contribution of hybrid 3-tier grading of bladder cancer and how this could impact the classification of papillary urothelial neoplasms and shape future grading scheme proposals.	bladder
Unraveling the dual role of METTL3-mediated m(6)A RNA modification in bladder cancer: mechanisms, therapeutic vulnerabilities, and clinical implications.	Bladder cancer (BC) remains challenging due to its recurrence and metastasis, with METTL3-mediated m(6) A RNA modification emerging as a key oncogenic driver. This review synthesizes METTL3's roles in BC progression, including tumor initiation, metastasis, stemness, and therapy resistance. We detail its regulation of critical pathways (e.g. HIF1A/IGF2BP3/BIRC5, AFF4/NF-κB/c-MYC) and dual functions in RNA stability and epigenetic crosstalk with DNA methylation. METTL3 promotes chemoresistance (e.g. circ0008399/WTAP/TNFAIP3) and immune evasion (PD-L1 stabilization), while its overexpression correlates with poor prognosis and cisplatin resistance. By integrating METTL3's interactions with m(6) A readers (YTHDF1/2, IGF2BP3) and erasers (ALKBH5), we propose targeting METTL3 as a strategy to enhance chemotherapy and immunotherapy efficacy. This work underscores METTL3's potential as a diagnostic biomarker and therapeutic target, advancing precision oncology in BC.	bladder
Treatment-Related Adverse Events and Associated Outcomes in Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis of the UNITE Study.	INTRODUCTION: Enfortumab vedotin-ejfv (EV), an antibody-drug conjugate approved for advanced urothelial carcinoma (aUC), has limited real-world safety data and no validated predictive biomarkers. Retrospective studies suggest higher objective response rates (ORR) among patients developing EV-related dermatologic toxicities, but survival implications remain unclear. This analysis assessed the safety of EV monotherapy and the impact of dermatologic and neurologic toxicities on efficacy outcomes in a multi-institutional cohort. MATERIALS AND METHODS: UNITE is a multicenter, retrospective study across 16 US sites of patients with aUC treated with targeted agents, including EV. Primary endpoints were the incidence of EV treatment-related adverse events (TRAEs, any grade) and TRAE-related treatment modifications. Secondary endpoints included a comparison of ORR, progression-free survival (PFS), and overall survival (OS) between patients with and without dermatologic toxicities and neuropathy. To reduce immortal time bias, Cox regression models incorporated TRAEs as time-dependent covariates to adjust for EV treatment duration as well as Eastern Cooperative Oncology Group performance status (ECOG PS), hemoglobin, and liver metastases. RESULTS: Between 2018 and 2023, 485 patients with aUC received > 1 dose of EV monotherapy. Most (67%) received > 2 prior therapy lines. Any grade TRAEs occurred in 77%, most frequently neuropathy (36%) and dermatologic toxicities (27%); 57% required treatment modification and 21% discontinued EV, primarily due to neuropathy (9%) and fatigue (3%). Patients with dermatologic toxicities and neuropathy had higher ORR (56% vs. 42%; p = 0.007 and 64% vs. 35%; p < 0.0001, respectively). Neuropathy was independently associated with improved OS (HR 0.66; 95% CI 0.50-0.87; p = 0.002); dermatologic TRAEs were not associated with PFS or OS benefit. CONCLUSIONS: EV safety outside clinical trials was consistent with prior reports, with no new signals. Treatment modifications were most often due to neuropathy, dermatologic toxicities, and fatigue. Both dermatologic toxicities and neuropathy correlated with higher ORR, but only neuropathy was independently associated with improved OS.	bladder
ALBAN (GETUG-AFU 37): a phase III, randomized, open-label international trial of intravenous atezolizumab and intravesical Bacillus Calmette-Guérin (BCG) versus BCG alone in BCG-naive high-risk, non-muscle-invasive bladder cancer (NMIBC).	BACKGROUND: Standard treatment of high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor is intravesical instillation with Bacillus Calmette-Guérin (BCG) (induction and maintenance regimens); however, BCG therapy still fails in 30%-40% of patients. Prior studies suggest that programmed death-ligand 1 (PD-L1) expression and alterations in immune infiltration might be associated with BCG failure. PATIENTS AND METHODS: The ALBAN trial is an international, 1 : 1 randomized, open-label phase III trial comparing the combination of atezolizumab (an anti-PD-L1 antibody) and BCG (arm B) versus BCG alone (arm A) for BCG-naive patients with high-risk NMIBC. The primary endpoint was investigator-assessed event-free survival (EFS). Key secondary endpoints included high-grade recurrence-free survival, complete response rate, and duration of response in patients with carcinoma in situ disease, as well as overall survival. RESULTS: In total, 255 patients were randomly assigned to arm A and 262 to arm B. The trial did not meet its primary endpoint; there was no significant difference in EFS between arms, with a hazard ratio of 0.98 (95% confidence interval 0.71-1.36, P = 0.9106). EFS results were consistent across all prespecified subgroups. The safety profile of the treatment combination was consistent with that of the individual agents but showed higher rates of treatment-related adverse events (TRAEs) and grade ≥3 TRAEs than BCG alone. CONCLUSION: This phase III trial in BCG-naive patients with high-risk NMIBC did not demonstrate an EFS benefit from the addition of atezolizumab to 1-year BCG therapy, in contrast to positive EFS results reported with another PD-(L)1 agent, suggesting that any benefit from checkpoint-BCG therapy may be context- and agent-specific rather than a class effect. Future research should focus on biomarker-driven patient selection and optimization of the timing, duration, and route of checkpoint delivery relative to BCG.	bladder
Bladder Cancer and Vesical Imaging-Reporting and Data System: An Updated Review.	Bladder cancer is a prevalent malignancy with a significant societal burden. Treatment strategies and prognosis are largely determined by the degree of local tumor invasion into the bladder wall. The Vesical Imaging-Reporting and Data System (VI-RADS) is a standardized, MR imaging-based scoring system specifically designed to assess muscular invasion in bladder cancer. VI-RADS effectively differentiates between nonmuscle invasive bladder cancer and muscle-invasive bladder cancer. By providing an accurate and non-invasive evaluation of tumor depth, location, and stage, VI-RADS facilitates effective management of patients with bladder cancer.	bladder
SQLE drives bladder cancer progression by boosting mitochondrial oxidative phosphorylation.	Bladder cancer (BCa) remains a prevalent malignancy with limited therapeutic options. Although cholesterol elevation links to BCa progression, the specific role of cholesterol metabolism remains unclear. Here, we demonstrate that squalene epoxidase (SQLE), a key cholesterol biosynthesis enzyme, drives BCa oncogenesis. SQLE is upregulated in BCa patients and correlates with poor survival. Functionally, bladder-specific Sqle transgenic (tg) mice showed accelerated tumorigenesis, while Sqle knockout (ko) demonstrated opposite effects in vivo. Mechanistically, SQLE localizes to mitochondria and directly interacts with Lon peptidase 1 (LONP1) to stabilize mitochondrial transcription factor A (TFAM) by preventing its proteolysis, leading to elevated oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mtROS). Pharmacological clearance of mtROS via Mito-TEMPO suppressed tumor growth in Sqle-overexpressing models. Importantly, the FDA-approved SQLE inhibitor terbinafine significantly suppressed BCa progression in preclinical models. Our findings establish SQLE as a critical regulator of mitochondrial metabolism in BCa, supporting SQLE inhibitors as potential therapeutics. In bladder cancer, overexpression of SQLE impairs LONP1-mediated TFAM degradation through direct interaction with LONP1, thereby leading to increased mitochondrial OXPHOS and the accumulation of mtROS, which ultimately contributes to tumor growth. Treatment with the SQLE inhibitor terbinafine effectively blocks this process, providing a potential therapeutic strategy to inhibit tumor progression. The Graphical Abstract was created using Smart.Servie ( https://smart.servier.com/citation-sharing/ ).	bladder
The role of lasers in the management of bladder tumors.	INTRODUCTION: The objective of this review is to assess the role of laser technology in the management of non-muscle-invasive bladder cancer (NMIBC). METHODS: A literature review was conducted using the Medline database with the keywords bladder and laser. Relevant articles in English and French were selected to produce a narrative review focusing on the main risks and applications of lasers in urology. RESULTS: The lasers currently employed for NMIBC treatment include Ho:YAG, continuous and pulsed Tm:YAG, thulium fiber, GreenLight KTP or LBO, and diode lasers. Two surgical techniques are currently used for endoscopic laser management of NMIBC: en bloc resection and photovaporization. Laser settings according to surgical technique and generator type, as well as oncological, histological, and safety outcomes, are discussed in this review. Overall, lasers occupy an important role in NMIBC management, offering oncological results comparable to other energy sources while providing a more favorable perioperative safety profile. CONCLUSION: Despite favorable outcomes, further studies are required to better define the role of lasers in NMIBC management through randomized controlled trials with long-term follow-up. Such evidence would help clarify the specific indications of each laser modality and optimize the surgical treatment of NMIBC with laser technology.	bladder
Targeted therapies for Bacillus Calmette-Guérin unresponsive nonmuscle-invasive bladder cancer: a narrative review.	PURPOSE OF REVIEW: The purpose of this narrative review is to compile the latest available evidence on targeted therapy in the management of Bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle-invasive bladder cancer (NMIBC). RECENT FINDINGS: Several recent studies have reported promising results for anti-fibroblast growth factor receptor (FGFR) (erdafitinib) in patients with advanced or metastatic urothelial carcinoma with FGFR alterations. These findings support the exploration of targeted therapies, including tyrosine kinase inhibitors (anti-FGFR and anti-vascular endothelial growth factor (VEGF)), mTOR inhibitors, and EpCAM inhibitors at an earlier stage of the disease to avoid or delay radical cystectomy. SUMMARY: The THOR-2 study demonstrated promising results for oral Erdafitinib in 73 high-risk BCG-unresponsive pTa/pT1 patients, showing 6 and 12-month recurrence-free survival rates of 96 and 77%, respectively. However, it was associated with notable adverse events (100%, including 22% serious). Other targeted therapies, such as Dovitinib (FGFR inhibitor), Sunitinib (VEGF inhibitor), and Everolimus (mTOR inhibitor), were assessed in three phase II studies, yielding disease-free survival rates between 8 and 44% over 3-12 months. Additionally, in a recent phase 3 trial involving 134 patients with BCG-unresponsive NMIBC, Oportuzumab Monatox (an EpCAM inhibitor) demonstrated a complete response rate of 40% at 3 months and a median response duration of 9.4 months.	bladder